1. ¹Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
2. ²State Key Laboratory for Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, Peoples Republic of China
3. ³Department of Biochemistry, Chinese University of Hong Kong, Shatin, Hong Kong
4. ⁴Shanghai Eastern Hospital and Institute of Hepatobiliary Surgery, Second Military Medical University, Shanghai, Peoples Republic of China
5. ⁵Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
6. ⁶Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Correspondence: Dr MA Feitelson, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Room 222 Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA. E-mail: Mark.Feitelson@jefferson.edu

⁷Drs Liu and Lian contributed equally to this study.

Received 14 June 2005; Revised 10 August 2005; Accepted 15 August 2005; Published online 10 October 2005.

Abstract

Hepatitis B virus (HBV)-encoded X antigen (HBxAg) contributes to the development of hepatocellular carcinoma (HCC). A frequent characteristic of HCC is reduced or absent expression of the cell adhesion protein, E-cadherin, although it is not known whether HBxAg plays a role. To address this, the levels of E-cadherin were determined in HBxAg-positive and -negative HepG2 cells in culture, and in tumor and surrounding nontumor liver from a panel of HBV carriers. The results showed an inverse relationship between HBxAg and E-cadherin expression both in tissue culture and in vivo. In HBxAg-positive cells, E-cadherin was suppressed at both the mRNA and protein levels. This was associated with hypermethylation of the E-cadherin promoter. Depressed E-cadherin correlated with HBxAg trans-activation function, as did the migration of HepG2 cells in vitro. Decreased expression of E-cadherin was also associated with the accumulation of -catenin in the cytoplasm and/or nuclei in tissues and cell lines, which is characteristic of activated -catenin. Additional work showed that HBxAg-activated -catenin. Together, these results suggest that the HBxAg is associated with decreased expression of E-cadherin, accumulation of -catenin in the cytoplasm and nucleus, and increased cell migration, which may contribute importantly to hepatocarcinogenesis.